Sertaconazole (INN-WHO) is an antifungal agent broadly used in the therapy of infections caused by fungi and yeasts in man an animals. Sertaconazole is 1-[2-(7-chlorobenzo[b]thiopheno-3-ylmethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole. Commonly sertaconazole is used as mononitrate salt (I).
EP 151477, which is merely cited as an illustration, discloses the preparation of sertaconazole mononitrate (I) by reacting 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (II) with sodium hydride and 3-bromomethyl-7-chlorobenzo[b]thiophene (III, L=Br) in hexamethylphosphoramide and treating the resulting sertaconazole free base with nitric acid.
Applicants have discovered that out of the two potential enantiomers of sertaconazole, the antifungal activity mainly lies in the R-(−)-enantiomer. It is, therefore, of a great interest to develop improved methods for manufacturing R-(−)-sertaconazole (IV) and its derived salts. R-(−)-sertaconazole (IV) and its preferred salt, the mononitrate (V), have been disclosed in WO 03068770. R-(−)-sertaconazole (IV) and R-(−)-sertaconazole mononitrate (V) are potent antifungal agents for medicinal, veterinary and agricultural use.
WO 03068770 discloses the preparation of R-(−)-sertaconazole (IV) by reacting R-(−)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-ethanol (VI) with 3-(chloromethyl or bromomethyl)-7-chlorobenzo[b]thiophene (III, L=Cl, Br) in N,N-dimethylformamide and in the presence of potassium t-butoxide as a base. The yield of this operation is only 25%. Thereafter, the mononitrate salt (V) is obtained by acidifying with nitric acid in a mixture of ethanol and water (yield=89%). Overall yield of the process is then 22% only.